tbuckley/cabot-search huggingface dataset:
<i>QuickStats:</i> Percentage Distribution of Heat-Related Deaths,* by Age Group — National Vital Statistics System, United States, 2018–2020
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

74 75-84 ≥85 Percentage of heat-related deaths Age group, yrs * Deaths associated with exposure to natural heat were defined as deaths with any underlying or contributing causes of death having International Classification of Diseases, Tenth Revision codes X30, P81.0, or T67.Any records including code W92 ("Exposure to excessive heat of man-made origin") were excluded.In total, 3,066 heat-related deaths occurred during 2018-2020.During 2018-2020, a total of 3,066 heat-related deaths occurred.The highest percentage of heat-related deaths occurred among persons aged 55-64 years (19%), and the lowest percentage occurred among those aged 5-14 years (1%).Among those aged 5-14 through aged 55-64 years, the percentage of heat-related deaths increased with age, then decreased through those aged ≥85 years (7%).Approximately 2% of heat-related deaths occurred among those aged <1 year and 4% among those aged 1-4 years.
Abstract 4096: Development of novel anticancer RNA therapeutics with dual-targeting siRNA that silences ubiquitin family members
Authors: David O. Azorsa, David W. Lee, Marvin O'Ketch, Nathalie A. Azorsa, Ioanna Papacharalampous, Lizette A. Castaño, Jeffrey A. Kiefer, Spyro Mousses
Journal: Cancer Research (2022)

Abstract Ubiquitination is a metabolic process in eukaryotic cells that modifies proteins with ubiquitin leading to protein degradation via the ubiquitin-proteosome pathway. Cellular levels of ubiquitin are driven by the expression of RPS27A, UBA52, UBB and UBC. In cancer, the dysregulation of ubiquitination can affect various aspects of tumor progression including cell cycle regulation and gene expression. Ubiquitin B (UBB) gene has been shown to be over-expressed in some tumor types, including NSCLC and cervical cancer, and under-expressed in other tumors, in particularly a subset of ovarian cancers. A role for ubiquitin C (UBC) in cancer has not been well established but UBC has been described as a biomarker in renal cancer and CLL. In recent studies, repression of UBB in ovarian cancer cells was associated with sensitivity to UBC knockdown and demonstrated a synthetic lethal relationship. Since both UBB and UBC show substantial sequence homology, we explored the possibility of developing dual targeting siRNA that would silence both UBB and UBC. We identified unique individual siRNA sequences that efficiently silenced both UBB and UBC and led to rapid cytotoxicity in several cancer cell lines including the colon cancer cell line HCT-116, the breast cancer cell line SK-BR3, and the prostate cancer cell line 22Rv1. Treatment with either UBB-specific or UBC-specific siRNA did not show the same lethal phenotype. Dose response assays using the dual targeting siRNA designated U21 indicated EC50 for cytotoxicity between 50–500 pM in several cancer lines. Treatment of cancer cell lines with U21 leads to rapid apoptosis and cell death. Chemical modifications to pharmacologically stabilize the U21 siRNA sequence did not change its activity. The efficient cytotoxic activity of the U21 siRNA sequence has been integrated into our SeekR™ platform to create aptamer-siRNA chimeras for targeted delivery of the lethal U21 payload to specific cancer cell types. Citation Format: David O. Azorsa, David W. Lee, Marvin O'Ketch, Nathalie A. Azorsa, Ioanna Papacharalampous, Lizette A. Castaño, Jeffrey A. Kiefer, Spyro Mousses. Development of novel anticancer RNA therapeutics with dual-targeting siRNA that silences ubiquitin family members [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4096.
Abstract 129: Effect of punicic acid on MCF7 breast cancer cells
Authors: Oluwafemi Gbayisomore, Hannah Klausner, Shelley A. Phelan
Journal: Cancer Research (2022)

Abstract The pomegranate fruit has long been recognized for its health benefits in a wide range of chronic diseases. Components of pomegranate seed extracts (PSOs) have been shown to have antioxidant, anti-glycemic, and antimicrobial activity, and recent research has demonstrated that PSOs can inhibit the growth of select cancers in vitro. One of the main components of PSO is punicic acid, an omega-5 fatty acid that is capable of inhibiting breast and prostate cancer cell proliferation, although the mechanisms of action are not yet known. In order to further understand its potential anti-cancer properties, we investigated the effect of punicic acid on proliferation and viability of human MCF7 breast cancer cells. Cells were treated with various concentrations of punicic acid (between 10 and 100ug/ml) for up to 72 hours, and various endpoints were measured including cell proliferation, cytotoxicity, and apoptosis. We found that all doses led to a significant reduction in cell viability based on an MTS assay. We also found a dose-dependent effect of punicic acid on cytotoxicity, as measured by an LDH release assay. Cell death was confirmed to be, at least in part, due to apoptosis, as detected by Annexin V and propidium iodide fluorescence. While 10 ug/ml punicic acid induced measurable cell death by 48 hours, higher concentrations were toxic to cells within the first 24 hours of treatment. Since many of the peroxiredoxin (Prdx) family of antioxidant proteins are known to involved in cancer cell survival, and our lab previously demonstrated their regulation in MCF7 cells, we examined the effect of punicic acid on Prdx expression. We found members of this gene family to be significantly elevated within 24 hours of punicic acid treatment. Altogether, our data definitively demonstrates anti-cancer properties of punicic acid, as well as its ability to regulate antioxidant gene expression in these cells. This research has important implications in the field of natural products as therapeutic options for cancer treatment, as opposed to conventional chemotherapy. Citation Format: Oluwafemi Gbayisomore, Hannah Klausner, Shelley A. Phelan. Effect of punicic acid on MCF7 breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 129.
Abstract 5666: MyD88 in myofibroblasts regulates aerobic glycolysis-driven hepatocarcinogenesis via ERK-dependent PKM2 nuclear relocalization and activation
Authors: Qi Yuan, Jinhua Zhang
Journal: Cancer Research (2022)

Abstract Hepatic stellate cells (HSCs) and cancer-associated fibroblasts (CAFs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). MyD88 controls the expression of several key modifier genes in liver tumorigenesis; however, whether and how MyD88 in myofibroblasts contributes to the development of fibrosis-associated liver cancer remain elusive. Here, we used an established hepatocarcinogenesis mouse model involving apparent liver fibrogenesis, in which MyD88 was selectively depleted in myofibroblasts. Myofibroblast MyD88-deficient (Fib-MyD88 KO) mice developed significantly fewer and smaller liver tumor nodules. MyD88 deficiency in myofibroblasts attenuated liver fibrosis and aerobic glycolysis in hepatocellular carcinoma tissues. Mechanistically, MyD88 signaling in myofibroblasts increased the secretion of CCL20, which promoted aerobic glycolysis in cancer cells. This process was dependent on the CCR6 receptor and ERK/PKM2 signaling. Furthermore, liver tumor growth was greatly relieved when the mice were treated with a CCR6 inhibitor. Our data revealed a critical role for MyD88 in myofibroblasts in the promotion of hepatocellular carcinoma by affecting aerobic glycolysis in cancer cells and might provide a potential molecular therapeutic target for HCC. Citation Format: Qi Yuan, Jinhua Zhang. MyD88 in myofibroblasts regulates aerobic glycolysis-driven hepatocarcinogenesis via ERK-dependent PKM2 nuclear relocalization and activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5666.
Abstract 1786: SM-88, D/L-alpha-metyrosine, is a novel anti-cancer agent in estrogen receptor positive breast cancer
Authors: Diane M. Demas, Julie Collins, Ayesha N. Shajahan-Haq
Journal: Cancer Research (2022)

Abstract Breast cancer is the second most common cause of death from cancer in women in the United States after lung cancer. Estrogen receptor positive (ER+) breast cancer comprises 70% of all breast cancer cases. Antiestrogens and CDK4/6 inhibitors are now part of standard of care therapies for advanced and metastatic ER+ breast tumors. Unfortunately, resistance to these therapies is prevalent and metastatic breast cancer remains an incurable disease. Since drug resistant cancer cells often have deregulated metabolic pathways, we tested the efficacy of a novel dysfunctional tyrosine, SM-88 (D,L-alpha-metyrosine; racemetyrosine), alone or in combination with sub-toxic doses of conditioning agents, methoxsalen, phenytoin, and sirolimus (MPS) in resistant cell models of ER+ breast cancer. In normal cells, tyrosine, a non-essential amino acid, is made from phenylalanine and not readily taken up by cells. Therefore, it is hypothesized that SM-88 uptake will be increased in cancer cells compared to normal cells. To evaluate whether SM-88 is a potential anti-cancer agent for drug resistant ER+ tumors, we used antiestrogens and CDK4/6 inhibitors sensitive (parental MCF7 and T47D cell lines) or resistant (MCF7-R and T47D-R) cells in this study. We show that cell proliferation was inhibited in both sensitive and resistant ER+ breast cancer cells at 72 h, however, the IC50 of SM-88 as a monotherapy was higher in resistant cells compared with sensitive cells, 5mM versus 2 mM, respectively. Combination of SM-88 and MPS had an additive effect and lowered the IC50 in both resistant and sensitive cells, 2mM versus 1mM, respectively. Both LAT1 and CD98, known transporters of tyrosine, were expressed in sensitive and resistant cells. Furthermore, SM-88 as a single agent or in combination with MPS resulted in the induction of incomplete autophagy in both sensitive and resistant cells. Apoptosis and DNA damage was noted in p53-wildtype MCF7 and MCF7-R but not in p53-mutant T47D and T47D-R cells with SM-88 monotherapy or in combination with MPS. Ongoing work is focused on further defining the biochemical pathways in drug sensitive and resistant cells that will further support the current clinical use of SM-88 in advanced ER+ breast cancer (ClinicalTrials.gov Identifier: NCT04720664). Collectively, we show that SM-88 is potentially a novel anti-cancer agent in drug resistant ER+ breast cancer. Citation Format: Diane M. Demas, Julie Collins, Ayesha N. Shajahan-Haq. SM-88, D/L-alpha-metyrosine, is a novel anti-cancer agent in estrogen receptor positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1786.
Abstract 784: Andrographolide altered inflammation pathways and cytokine expression in prostatecancer
Authors: Mitzy J. Santiago Rosario, Gabriela Erazo Carde, María Sánchez Vázquez, Valerie Cardona, Magaly Martínez Ferrer
Journal: Cancer Research (2022)

Abstract Prostate cancer is the most diagnosed cancer in men in the USA. Andrographolide (AG) is a labdane diterpenoid compound isolated from the medicinal plant Andrographis paniculata. Previous studies in our laboratory showed that Andrographolide decreased prostate tumor size in mice, induced expression of DNA repair genes associated with double-strand break repair and altered mitochondrial function. The objective of this study is to determine the role of AG in inflammation in prostate cancer. Microarray analysis of tumors treated with Andrographolide 10 mg/kg and their vehicle were conducted. Tumors were developed using a xenograft model in which the prostates of SCID mice were injected with 22RV1, and mice were treated three times per week with Andrographolide 10 mg/kg. Tumor tissues were collected and snap frozen. Gene expression was identified and analyzed using the Affymetrix GeneChip® Human Gene 2.0 array. Using Ingenuity Pathway Analysis (IPA) we found that Andrographolide 10 mg/kg altered genes associated with inflammatory response such as ATM, DHFR, HIF-1-α, CDKAL1, DHFR, NOX1, C5, CCL4, COG6, SUPT20H, CA5B, TTC3. To determine changes of cytokine expression in PC3 prostate cancer cells treated with 25 μM Andrographolide, we used the Abcam Cytokine Antibody Array test®. PC3 prostate cancer cells treated with Andrographolide showed altered expression of cytokines such as IL-2, TNF-α, TNF-β, EGF, IGF-1, ENA-78, GM-CSF, GRO, GRO-α, I-309, and Angiogenin. These results showed that AG may alter the tumor microenvironment promoting the secretion of diverse cytokines that may inhibit tumor development. Understanding these biological pathways and networks is essential to determine possible targets of Andrographolide in prostate cancer. Citation Format: Mitzy J. Santiago Rosario, Gabriela Erazo Carde, María Sánchez Vázquez, Valerie Cardona, Magaly Martínez Ferrer. Andrographolide altered inflammation pathways and cytokine expression in prostatecancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 784.
Abstract 5366: Hotspot mutations of TP53 sensitize APC-mutated colorectal cancer cells to cetuximab <i>in vitro</i>
Authors: Mingli Yang, Heiman Wang, Thomas B. Davis, Lance Pflieger, Ramya Thota, W. Jack Pledger, Timothy J. Yeatman
Journal: Cancer Research (2022)

Abstract EGFR inhibitor (EGFRi) therapies (cetuximab and panitumumab) have been approved for metastatic CRC patients who harbor wild-type KRAS/NRAS. Unfortunately, only ~50% of treated patients will respond to therapy. While FDA approved for first-line therapy, these agents are seldom used, significantly limiting their utility. Thus, there is an unmet need to develop additional biomarkers to identify EGFRi sensitive patients. Using an innovative hybrid approach fusing gene expression and DNA sequencing, we recently reported that combined mutations in APC and TP53, two major tumor suppressor genes, were strongly correlated with a validated gene expression signature measuring cetuximab sensitivity (CTX-S) in 468 CRC human tumors (Yang et al. Cancer Epidemiol Biomarkers Prev. 2019). Further analysis reported that APC and TP53 mutations predict cetuximab sensitivity across consensus molecular subtypes (CMS1-4) (Thota et al. Cancers. 2021). While APC truncated mutations are known to mediate WNT pathway activation, one of key features of CMS2 CRCs reported to be associated with cetuximab response, little is known about TP53 mutations with cetuximab sensitivity. To investigate a contributive role of mutant TP53 in vitro, we stably transfected expression plasmids of three hotspot mutations (R175H, R248W, R273H) of TP53 in APC-mutated CRC cells such as SW48 cells harboring WT KRAS/NRAS. Multiple stable clones for each of three TP53 mutations (empty vector as a control) were selected for biochemical and RNASeq analyses. We found that the three oncogenic mutations of TP53 enhanced cetuximab-mediated apoptosis under low serum culture conditions (2% FBS). Interestingly, the enhanced drug effect was associated with altered p53 pathway signatures as assessed by RNASeq. In support of the role of TP53 mutations, siRNA-knockdown of TP53 in SW48 cells also demonstrated an increased sensitivity to cetuximab treatments. Collectively, these in vitro analysis supports TP53 mutations, in combination with APC mutations, as predictive mutation biomarkers of cetuximab sensitivity in CRC. Citation Format: Mingli Yang, Heiman Wang, Thomas B. Davis, Lance Pflieger, Ramya Thota, W. Jack Pledger, Timothy J. Yeatman. Hotspot mutations of TP53 sensitize APC-mutated colorectal cancer cells to cetuximab in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5366.
Abstract 4202: Dual chlorotoxin and methylguanine-DNA methyltransferase (MGMT) γδ-T cells for drug resistant immunotherapy
Authors: Lei Ding, Yanjie Li, Evan Klumpp, Lawrence Lamb
Journal: Cancer Research (2022)

Abstract High-grade gliomas are the most aggressive and refractory of brain tumors. Historical approaches to treating glioblastoma (GBM) using chimeric antigen receptor modified T cells (CAR-T) have been challenging, without a lasting benefit to patients, often due to tumor heterogeneity and a lack of tumor specific antigens. We report preliminary in vitro design and optimization of a γδ T cell-based CAR-T using Chlorotoxin (CLTX-CAR), a peptide isolated from the venom of the Israeli Deathstalker Scorpion that efficiently binds to GBM and other tumor cells with limited cross reactivity to normal tissues. This CLTX-CAR (CTLX-CAR-noZ) omits a CD3z signaling domain to maintain the natural innate targeting and tumor recognition properties of the γδ T cell through its endogenous T cell and NKG2D receptors, and CD16-based antibody-dependent cellular cytotoxicity (ADCC). This construct also includes our Drug Resistant Immunotherapy (DRI) platform that incorporates an additional p140K-MGMT encoding gene into the construct. This confers resistance to alkylating agents such as temozolomide (TMZ) that allows our DRI γδ T cells to remain viable and functional when combined with chemotherapy to force high-expression of natural killer group D ligands (NKG2DL) on the surface of tumor cells. As expected, the non-signaling, CLTX-CAR-noZ modified Jurkat cells did not result in T cell activation, as compared to the highly activated CD69 corresponding to signaling CLTX-CAR-CD3z transduced Jurkat cells. Conversely, CTLX-CAR-noZ transduced γδ T cells demonstrated higher cytotoxicity against U87MG and U251MG GBM cell lines over unmodified control γδ T cells. Dual-CLTX-CAR constructs lacking CD3z and using 2x CLTX peptides as the targeting domain (dCLTX-CAR-noZ) exhibited up to 90% lentiviral transduction efficiency into γδ T cells. When co-cultured in suspension with GBM cells in vitro, dCLTX-CAR-noZ γδ T cells demonstrated an average cytotoxicity of 62.1% against U87MG-GFP cells at an E:T ratio of 4:1 in comparison to 35.4% with non-transduced γδ T control cells. Time-lapsed microscopic recording over a period of 15hrs also verified killing of U251MG-GFP cells by dCLTX-CAR-noZ γδ T cells when cocultured with GBM cells at an E:T ratio of 2:1. Serial-killing of tumor cells by γδ T cells was documented. We are advancing this approach to xenograft animal models and as a clinical development candidate (INB-300) for both GBM and other extracranial tumors. Citation Format: Lei Ding, Yanjie Li, Evan Klumpp, Lawrence Lamb. Dual chlorotoxin and methylguanine-DNA methyltransferase (MGMT) γδ-T cells for drug resistant immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4202.
Abstract 6009: Developing drug-induced resistant tumor models for efficacy evaluation of next-generation anticancer therapies
Authors: Ting Ni, Gaoxiang Liu, Tongxin Huo, Wenting Shi, Qingyang Gu, Qunsheng Ji
Journal: Cancer Research (2022)

Abstract The therapeutic landscape of cancer has been transformed over the last few decades. Our understanding of cancer and its therapeutic approach has improved greatly due to advanced cancer biology, functional imaging and next-generation sequencing. One of the key challenges in cancer therapy is how to effectively kill cancer cells while leaving normal cells intact. As specific oncogenic drivers have been successfully identified, targeted treatments have achieved great success in clinical practice. However, acquired drug resistance remains the major barrier to sustained success of targeted cancer therapy. Those patients who initially respond well to targeted therapies eventually become resistant to the treatments. Uncovering the underlying mechanism would help develop novel therapies that overcome the drug resistance.To mimic the clinical resistance after long-term drug treatment, we established a panel of drug-induced resistant tumor models by continuous dosing of targeted drugs to tumor-bearing mice or cancer cell lines, covering a series of first-line targeted drugs including Sotorasib, Palbociclib, Ibrutinib, Capmatinib, Fulvestrant, Tamoxifen and TDM-1. Resistant models were derived from sensitive ones harboring specific oncogenic drivers. After treated with targeted drugs and passaged several times, resistant models exhibited stable resistance phenotype. Given that target gene mutation, alternative pathway activation or tumor microenvironment evolution could promote therapy resistance and cancer progression, we performed transcript and protein analysis to explore the molecular mechanism, and evaluated the potential therapeutic strategies overcoming drug resistance in the established models. Taken together, drug-induced resistant tumor models provide a promising opportunity to the better understanding of drug resistance mechanisms and to the accelerated development of next-generation anticancer agents. Citation Format: Ting Ni, Gaoxiang Liu, Tongxin Huo, Wenting Shi, Qingyang Gu, Qunsheng Ji. Developing drug-induced resistant tumor models for efficacy evaluation of next-generation anticancer therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6009.